Aging is a major risk factor of human cancers. Our project is to elucidate molecular mechanisms of aging and cancer using cellular and animal models. We have shown that normal human cells have telomerase-dependent and independent pathways for cellular senescence, which both serve as a tumor suppressive mechanism. The senescence genes on chromosome 3p21 (a transcriptional repressor of the telomerase hTERT gene) and chromosome 1q42.3 (which functions independently of telomerase regulation) are to be cloned by the positional and functional cloning methods. To understand a link between cellular aging and organismal aging, we study SIRTs, human homologs of the yeast/worm longevity gene Sir-2 encoding a NAD-dependent protein deacetylase. Our data suggest the more complex regulation of aging processes in humans than in yeast or worms and multiple functions of human SIRT proteins at different cellular locations (i.e., nucleus, nucleolus, cytoplasm and mitochondria). We have found that DNA double-strand breaks (DSB) accumulate in mammalian cells during both cellular senescence and in vivo aging, providing important insight into the mechanism by which cellular senescence contribute to organismal aging. We are also examining how various local or systemic conditions (e.g., hypoxia, oxidative stress, obesity, calorie intake) affect the above-mentioned pathways/factors to regulate human aging and carcinogenesis processes.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC010417-05
Application #
7053948
Study Section
(LBC)
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2004
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Sedelnikova, Olga A; Horikawa, Izumi; Zimonjic, Drazen B et al. (2004) Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks. Nat Cell Biol 6:168-70
Tsutsui, Takeki; Tamura, Yukiko; Yagi, Eiichi et al. (2003) Cell-transforming activity and mutagenicity of 5 phytoestrogens in cultured mammalian cells. Int J Cancer 105:312-20
Horikawa, Izumi; Barrett, J Carl (2003) Transcriptional regulation of the telomerase hTERT gene as a target for cellular and viral oncogenic mechanisms. Carcinogenesis 24:1167-76
Shigeeda, Nobumasa; Uchida, Minoru; Barrett, J Carl et al. (2003) Candidate chromosomal regions for genes involved in activation of alternative lengthening of telomeres in human immortal cell lines. Exp Gerontol 38:641-51
Kenney, Nicholas J; Bowman, Arthur; Korach, Kenneth S et al. (2003) Effect of exogenous epidermal-like growth factors on mammary gland development and differentiation in the estrogen receptor-alpha knockout (ERKO) mouse. Breast Cancer Res Treat 79:161-73
Yawata, Toshio; Kamino, Hiroki; Kugoh, Hiroyuki et al. (2003) Identification of a Oncogene 22:281-90
Yamamoto, Akito; Kumakura, Shin-ichi; Uchida, Minoru et al. (2003) Immortalization of normal human embryonic fibroblasts by introduction of either the human papillomavirus type 16 E6 or E7 gene alone. Int J Cancer 106:301-9
Yin, Yuxin; Liu, Yu-Xin; Jin, Yan J et al. (2003) PAC1 phosphatase is a transcription target of p53 in signalling apoptosis and growth suppression. Nature 422:527-31
Li, Shuanfang; Hursting, Stephen D; Davis, Barbara J et al. (2003) Environmental exposure, DNA methylation, and gene regulation: lessons from diethylstilbesterol-induced cancers. Ann N Y Acad Sci 983:161-9
Li, Shuanfang; Hansman, Roberta; Newbold, Retha et al. (2003) Neonatal diethylstilbestrol exposure induces persistent elevation of c-fos expression and hypomethylation in its exon-4 in mouse uterus. Mol Carcinog 38:78-84

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